IN-VITRO HEPATIC BIOTRANSFORMATION OF MOCLOBEMIDE (RO 11-1163) IN MANAND RAT

1. Moclobemide, an inhibitor of monoamine oxidase, shows mixed MAO A/B inhibition in rat, but pure MAO A inhibition in man. This is attribut ed to a primary amine metabolite which inhibits MAO B in vitro, but wh ich is not detected in human plasma in vivo. A secondary amine metabol ite, also present in rat but not human plasma, inhibits MAO B in vivo but not in vitro. 2. We have studied the biotransformation of moclobem ide in vitro, to investigate whether hepatocytes and hepatic subcellul ar fractions can reproduce the in vivo interspecies differences. 3. Mo clobemide was more extensively metabolized by rat liver preparations, compared with man. For example, of an initial 100nmol, 78 and 25nmol w ere metabolized within 24h by rat and human hepatocytes in primary cul ture, respectively.4. Substantial amounts of secondary amine (12.5 nmo l) were found with the rat preparation, compared with low amounts (1.5 nmol) from human hepatocytes. Similarly, for the primary amine, 1.5 n mol were formed by the rat hepatocytes compared with trace amount in t he human preparations. 5. Identities of the two amines were confirmed by h.p.l.c. cochromatography and negative CI GC-MS. 6. In conclusion, all the in vitro models, but particularly hepatocytes, reflected the m etabolism of moclobemide in vivo. Consequently, liver preparations can be used prospectively to screen the selectivity of related developmen t compounds.